This invention relates to regimens of administering compounds, which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997, published Jul. 4, 1996). PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991). PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline A. 
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al, disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad Sci., 761, 383, 1995). 
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). 
Kurihari, et al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). 
Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and NO2. 
wherein: R4=H, Ar, R11, OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), xe2x80x94S(O)qR11, N(R6)2, XR11, halogen or NHCOR6; X=(CH2)n, O, NR6 or S(O)q; n=0-6; q=0-2; R6=H or 1-4 C alkyl; R11=1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynl (all optionally substituted); Ar=(i) optionally substituted phenyl or benzo-fused group of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, iridazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrirndyl, all optionally substituted by one or more R1 or R2 groups. 
U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2 to 4 days to prevent breakthrough bleeding.
This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, and prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effective dose or minimization of side effects or cyclic menstrual bleeding.
The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14 to 24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 pg to about 150 xcexcg levonorgestrel per day, preferably equal in activity to from about 35 xcexcg to about 100 xcexcg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 xcexcg to about 50 xcexcg per day and the estrogen may be administered at a dose of from about 10 xcexcg to about 35 xcexcg per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with an estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimnate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28. It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28-day cycle. In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This may be followed as described above with an antiprogestin administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28.
Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 xcexcg. From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo.
This invention also provides kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated.
According to the regimens described above, one 28-day kit may comprise:
a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to from about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.
A preferred embodiment of this kit may comprise:
a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
Another 28-day cycle packaging regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of from 1 to 7 daily dosage units of an antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the kit described above may comprise:
a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin administered at a daily dose of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
A further 28-day packaged regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the package or kit just described comprises:
a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be administered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art.
In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.
These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated.
Compounds of this invention that may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula I: 
wherein:
R1 and R2 are chosen independently from H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl;
or R1 and R2 are joined to form a ring comprising one of the following: xe2x80x94CH2(CH2)nCH2xe2x80x94; xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94; xe2x80x94O(CH2)mCH2xe2x80x94; O(CH2)pOxe2x80x94; xe2x80x94CH2CH2OCH2CH2xe2x80x94; xe2x80x94CH2CH2N(H or alkyl)CH2CH2xe2x80x94;
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
or R1 and R2 together comprise a double bond to xe2x95x90C(CH3)2; xe2x95x90C(C3-C6 cycloalkyl), xe2x95x90O, or xe2x95x90C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl or substituted alkynyl, or CORA;
RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4 is H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R5 is selected from the groups a), b) or c):
a) R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORB, OCORB, or NRCCORB;
RB is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 amioalkyl, or substituted C1 to C3 aminoalkyl;
RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl:
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkyl; or
b) R5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R6 is H or C1 to C3 alkyl; or
c) R5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO2, lower alkoxy, or CF3; wherein R6 and R7 are independently chosen from H, methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, cyclohexyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
or pharmaceutically acceptable salt thereof.
A preferred set of antiprogestin compounds of this invention is depicted by structure II: 
wherein:
R5 is a disubstituted benzene ring containing the substituents X, and Y as shown below: 
X is selected from halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2position selected from H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl; or
R5 is a five membered ring having the structure: 
U is O, S, or NR6,
R6 is H, or C1 to C3 alkyl, or C1 to C4CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, C1 to C3 alkyl or C1 to C3 alkoxy;
Yxe2x80x2 is selected from the group H, F, CN, NO2 or C1 to C4 alkyl; or
R5 is a six-membered ring with the structure: 
X1 is N or CX2;
X2 is halogen, CN or NO2;
or pharmaceutically acceptable salt thereof.
The antiprogestin compounds of the formulations and regimens of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I and II the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d refers to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term xe2x80x9caryloxyxe2x80x9d refers to the OR group, where R is aryl or substituted aryl, as defined above. The term xe2x80x9calkylcarbonylxe2x80x9d refers to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkylcarboxyxe2x80x9d indicates the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atom The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The antiprogestational compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
When the active compounds of these regimens are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The pharmacologically active agents of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The compounds of this invention can be prepared by the procedures outlined in the Schemes illustrated below:
Typically the antiprogestin compounds of this invention are prepared in a convergent manner as shown is Scheme 1, by a suitable coupling reaction. For example, a palladium mediated coupling of an aryl halide with an aryl boronic acid provides the desired bi-aryl substituted target. The choice of the aryl halide-aryl boronic acid combination is established experimentally. 
As outlined in Scheme 2, the xe2x80x9cright sidexe2x80x9d of the antiprogestin compounds of this invention may be prepared by following the procedure described of Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1993, Vol. 1, pp. 939-944. 
As an example the right side template, 2, is prepared by condensing an appropriately substituted phenyl hydrazine and a suitable ketone to give the corresponding hydrazone. This material is cyclized to an imine in refluxing acetic acid and then reduced to the desired indoline template 2. Examples 1-7 and 10-20 were prepared by this route using the appropriate ketone.
Alternatively the right side template may be prepared as outlined in Scheme 3. The commercially available oxindole is di-alkylated at C-3 by using an appropriate base and the corresponding alkyl halide to give the 3,3-dialky-oxindole, 8, or the spirocyclic oxindole 9. These oxindoles are then brorninated under standard conditions and the carbonyl group is reduced to the desired methylene using a hydride mediated reduction. The timing of the aryl coupling and the reduction of the 2-position carbonyl are established experimentally. 
The right side templates are coupled with an appropriate aryl boronic acid using an appropriate palladium (0) catalyst, Scheme 4. For example compound 10 is coupled under standard Suzuki conditions with an appropriately substituted aryl-boronic acid to afford compound 11. 
The compounds of this invention, are stable semi-solids and are conveniently converted into their corresponding salts by treatment with acid. Example 1, compound 11 (R1=R2=R3=Me), when treated with HCl in dioxane affords the HCl salt (Example 2) as a white solid. The racemic indolines can be separated into their enantiomers by Chiral HPLC1 to provide the individual enantiomers in  greater than 98% EE.